Project Summary FoxM1 is a forkhead-box family transcription factor that is over-expressed in a wide variety of human cancers, including cancers of liver, colon, lung and prostate. Its over- expression in prostate cancers correlates with metastasis. In mouse models, FoxM1 is essential for development liver carcinomas, and is required for tumor progression. For example, specific inhibition of FoxM1, by a peptide derived from the tumor suppressor p19Arf, causes regression of liver tumors in mice, suggesting a critical role for FoxM1 in survival of tumor cells. Also, several studies implicated FoxM1 as a potential anticancer drug target. However, the mechanisms by which FoxM1 participates in tumorigenesis and promotes survival of tumor cells are not clear. In this proposal, we plan to investigate a newly discovered function of FoxM1 in transformation and tumor cell survival, which will be significant in the considerations of FoxM1 as an anti-tumor drug target in drug resistant tumors. We observed that FoxM1 is activated by reactive oxygen species (ROS), and that oncogenic Ras activates FoxM1 requiring ROS. Moreover, we obtained evidence for a negative feed back mechanism for regulation of ROS in which the elevated FoxM1 down regulates ROS. The negative feed back loop is critical for survival of proliferating cells in the presence of excessive ROS. FoxM1 promotes survival of tumor cells by down regulating the levels of ROS. We plan to investigate the hypotheses that FoxM1 is the pivotal regulator of ROS in proliferating cells and in tumor cells, and that the tumors cells expressing ROS-inducing oncogenes are addicted to FoxM1. Moreover, we will determine whether over expression of FoxM1 in tumor cells confers resistance to therapies by down regulating ROS. These studies will establish the functions of FoxM1 in tumor development and progression, as well as establish a role of FoxM1 over expression in the development of drug resistance.